Structural basis of biological active β-amyloid conformers

生物活性β-淀粉样蛋白构象异构体的结构基础

• 批准号: 409798861
• 负责人: Professor Dr. Marcus Fändrich
• 金额: --
• 依托单位: Abteilung für Zellbiologie Neurologischer Erkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/409798861?language=en
• 关键词: Structural; basis; biological; active; amyloid

The deposition of beta-amyloid (Abeta) peptide as amyloid fibrils is ahallmark of neurodegenerative conditions, such as cerebral amyloidangiopathy (CAA) and Alzheimer´s disease (AD). Underlying theseevents is a molecular self-assembly reaction that can be seeded invitro by preformed amyloid fibrils and in vivo by intracerebral injectionof Abeta-containing brain extracts into Alzheimer mouse models.Increasing evidence shows that this effect is provoked by Abeta fibril.Abeta fibrils may also play a pathogenic role in CAA, althoughneurodegeneration in AD may rather depend on the toxic effect ofintermediate states. Conflicting structural models have been obtainedfor different preparations of Abeta fibrils or intermediates in vitro, whilethe structure of Abeta fibrils formed inside a diseased patient remainunclear. In this project we will purify Abeta fibrils from diseased humantissue to make it available for direct structural analysis with high end biophysical methods, including in particular electron microscopy.Expected results may be important for understandning the spreadingof neurodegenerative diseases.

β-淀粉样蛋白（Abeta）以淀粉样纤维的形式沉积是神经退行性疾病的标志，如脑淀粉样血管病（CAA）和阿尔茨海默病（AD）。这些事件的基础是一种分子自组装反应，这种反应可以在体外通过预先形成的淀粉样纤维接种，也可以在体内通过脑内注射含有A β的脑提取物接种到阿尔茨海默病小鼠模型中。越来越多的证据表明，这种作用是由A β纤维引起的。A β纤维也可能在CAA中起致病作用，尽管AD中的神经变性可能更依赖于中间状态的毒性作用。对于体外不同的Abeta原纤维或中间体制剂，已经获得了相互矛盾的结构模型，而在患病患者体内形成的Abeta原纤维的结构仍不清楚。在这个项目中，我们将从患病的人体组织中纯化Abeta原纤维，使其可用于高端生物物理方法的直接结构分析，特别是电子显微镜。预期结果可能对了解神经退行性疾病的传播很重要。